Compounds of the structural formula (I): ##STR1## wherein R.sub.1 is (L).sub.a --(CH.sub.2).sub.b --(T).sub.c --Q;
a is 0 or 1; PA0 b is 3 to 14; PA0 c is 0 or 1; PA0 L and T are independently oxygen or CH.sub.2 ; PA0 Q is C.sub.1-4 alkyl, trifluoromethyl, furanyl, thienyl, cyclohexyl or phenyl, optionally monosubstituted with Br, Cl, CF3, C.sub.1-4 alkoxy, or C.sub.1-4 alkyl; PA0 R.sub.2 and A are independently selected from H, CF.sub.3, C.sub.1-4 alkyl, halogen or NO.sub.2 ; or PA0 R.sub.1 is H and R.sub.2 is (L).sub.a --(CH.sub.2).sub.b --(T).sub.c --Q, wherein a, b, c, L, T and Q are as defined above; and PA0 R.sub.5 is lower alkyl, PA0 a is 0 or 1; PA0 b is 3 to 14; PA0 c is 0 or 1; PA0 L and T are independently oxygen or CH.sub.2 ; PA0 Q is C.sub.1-4 alkyl, trifluoromethyl, furanyl, thienyl, cyclohexyl or phenyl, optionally monosubstituted with Br, Cl, CF.sub.3, C.sub.1-4 alkoxy, or C.sub.1-4 alkyl; PA0 R.sub.2 and A are independently selected from H, CF.sub.3, C.sub.1-4 alkyl, halogen or NO.sub.2 ; or PA0 R.sub.1 is H and R.sub.2 is (L).sub.a --(CH.sub.2).sub.b --(T).sub.c --Q wherein a, b, c, L, T and B are as defined above; and PA0 R.sub.3 may be phenyl, substituted phenyl, naphthyl or substituted naphthyl, where the substituents may be one or two halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy or trifluoromethyl groups.
are useful intermediates in the synthesis of pharmaceutically important compounds, for example, leukotriene antagonists. Such compounds are disclosed in copending applications, U.S. Ser. Nos. 07/195,355, 07/066,588 and 07/066,592. Leukotriene antagonists are useful pharmaceutical compounds which have been used to treat the symptoms of asthma and bronchospasm in mammals. An example of such an antagonist is the compound 2(S)-hydroxy-3(R)-[2-(carboxyethylthio)]-3-[2-(8-phenyloctyl)phenyl]propio nic acid, which compound contains two chiral centers. As is often the case, optimal therapeutic activity is provided only by one configuration of the two chiral centers. It is therefore desirable to produce this material in a form which is highly enriched in only one absolute configuration of the chiral centers.
Current methods for preparing these pharmaceutical compounds proceed through the intermediacy of the racemic .alpha.-epoxy esters of formula (I). These compounds are produced via a Darzens condensation. Thus, substituted benzaldehydes of structural formula (V), ##STR2## wherein R.sub.1, R.sub.2 and A are as defined previously, are reacted with ethyl or methyl .alpha.-halo acetates to yield the desired .alpha.-epoxy esters. The substituted benzaldehydes are produced by methods common in the art, for example, Perchonock et al., J. Med. Chem., 29, 1442-52 (1986); Perchonock et al., J. Med. Chem., 28, 1145-47 (1985); and copending patent applications 07/195,355, 07/066,588 and 07/066,592, all of which are incorporated by reference.
The epoxy-esters produced in the Darzens condensation are reacted with a mercaptan, typically with a mercapto-alkyl or mercapto-aryl carboxylic acid ester to produce a hydroxy-sulfido ester. Upon hydrolysis of the diester, resolution of the enantiomers, via fractional crystallization of the salt formed with an optically active resolving agent, yields the optically pure leukotriene antagonist.
There are many methods for preparing .alpha.-epoxy esters of Formula (I). Among these well known methods are the Darzens condensation, alkaline peroxide oxidation of alkylidine malonic esters, peracid oxidation of .alpha.,.beta.-unsaturated esters and alkaline closure of halohydrins See for example, House, H. O., Modern Synthetic Reactions, 292-329, 422-436, W. A. Benjamin, Inc., Philippines (1972). However, all of these methods yield a racemic epoxide product. There has been a report of a chiral Darzens condensation, Abdel-Magid et al., Tet. Lett., 25, 3273-76 (1984), but it relies upon the use of expensive chiral auxillaries.
Methods for the production of non-racemic .alpha.-epoxy ketones are known. Annunziata et al., Tet. Lett., 26, 2471-74 (1985), report a condensation of phenacyl halides with benzaldehydes in the presence of bovine serum albumin. Other methods generally consist of alkaline peroxide oxidation of the .alpha.,.beta. unsaturated ketone in the presence of a chiral auxillary. In this regard, Marsman et al., J. Org. Chem., 44, 2312(1970) have reported the use of benzyl quininium chloride; Banfi et al., Synthetic Comm., 13, 12, 1049-52(1983) have reported the use of cyclodextrins; Colonna et al., Tet. Lett., 27, 3, 387-90(1986) have reported the use of bovine serum albumin; and Julia et al., Angew. Chem. Int. Ed. Engl., 19, 929-30(1980) have reported the use of polyamino acids. These procedures have had varying degrees of success, with perhaps the most promising stereochemical yields being obtained with oxidations in the presence of polyamino acids. Julia et al., Annales de Oimica, 79 102-4(1982) report chemical yields as high as 78-85% and enantiomeric excess (e.e.) of 78-93% for simple chalcones. However, these methods have proved ineffective for the substituted aryl products of this invention. In addition, the reaction conditions of Julia et al. require the use of either aromatic hydrocarbons or halocarbon solvents to obtain acceptable asymmetric induction in the product epoxide. In particular, hexane and cyclohexane are claimed to give very poor asymmetric induction. (See Julia et al., J. Chem. Soc. Perkin Trans. I. 1317-24(1982)). Aromatic hydrocarbon and halocarbon solvents are not favored for use in an industrial process due to their toxicity.
The conversion of a ketone to an ester has often been accomplished by the Baeyer-Villiger reaction. This involves the reaction of a ketone with a peracid followed by a rearrangement which inserts an oxygen between the carbonyl and one of the two substituents of the carbonyl. Electronic factors usually determine the relative ratio of the two possible products which may be obtained. However, since epoxides are well known to be acid labile, such a reaction has never been reported upon an aryl epoxy ketone.
Epoxy esters resulting from the Baeyer-Villiger reaction of a peracid with an .alpha.,.beta.-unsaturated ketone have been reported in the chemical art. However, in most cases a complex mixture of products is obtained in which only a portion of the products contain an epoxide and the Baeyer-Villiger rearrangement inserts oxygen between either the carbonyl and epoxide or the carbonyl and the double bond. .alpha.-Epoxy esters are disfavored and formed in only minor amounts, if at all. (See DeBoer et al., J. Org. Chem., 39, 1, 77-83(1974); Yokayama et al., Bull. Chem. Soc. Japan, 38, 9, 1498-1500(1965); Payne et al., J. Org. Chem., 24, 284-6(1959); Walton et al., J. Org. Chem., 22, 1161-5(1957)).
An unusual Baeyer-Villiger rearrangement has been reported to occur with hydrogen peroxide under alkaline conditions for certain 2-keto, .DELTA.-3 A-nor-steroids (Levine et al., J. Org. Chem., 31, 3189-92(1966) and Rucker, et al., Arch. Pharm., 317, 561-4(1984)) to produce an .alpha.-epoxy lactone. This is in contrast to results obtained with oxidations of other substrates with peroxides under alkaline conditions, which results exclusively in epoxidation.
The .alpha.-epoxy ketones and .alpha.-epoxy esters of this invention are new. In addition, excepting certain chalcones substituted in the 2-position by a C.sub.3-7 alkoxy group, the .alpha.,.beta.-unsaturated ketones of this invention, are also new. Examples of 2-alkoxy chalcones have been reported by Nagesam et al., Acta Cienc Indica Ser. Chem., 10, 165-9 (1984), Profft et al., J. Prakt. Chem., 19, 192-201 (1963) and Tsatsas et al., Prakt. Akad. Athenon, 35, 418-23 (1960).